Chronic inflammatory diseases and oxidative stress are major risk factors of colorectal cancer (CRC), the second-ranked cause of death among cancer patients. However, the mechanisms through which increased oxidative stress and inflammatory markers cause CRC are not well understood. Understanding these biochemical mechanisms, especially the role of increased reactive oxygen species (ROS) in the pathophysiology of CRC, will help in developing better therapeutic strategies. We have recently demonstrated that aldose reductase (AR) an enzyme that we have shown catalyzes the reduction of ROS-induced lipid aldehydes and their glutathione-conjugates (such as HNE and GS-HNE to DHN and GS-DHN),is an obligatory mediator of growth factor and cytokine-induced NF-:B activation in human colon cancer cells. Further, we have shown that AR inhibition or ablation by SiRNA prevents the growth of colon cancer cells in culture as well as in nude mice xenografts. Our long term goal is to understand the mechanisms by which AR contributes to CRC progression, and to develop AR inhibitors (ARIs) for chemoprevention of CRC. We will now systematically examine our hypothesis that the effects of ROS are in part mediated by AR- catalyzed reduced lipid peroxidation-derived aldehydes (LDAs) and their metabolites by investigating the role of AR in mediating growth factor-induced cancer growth in cultured cells, nude mice xenografts and murine models of CRC.
Our specific aims are 1) Investigate the effects of AR inhibition on the growth factor-induced progression of cultured human colon cancer cell growth, 2) Delineate the effects of AR inhibition/ablation on colon cancer progression in nude mouse xenografts, and 3) Delineate the chemopreventive efficacy of AR inhibition in chemically and genetically-induced CRC in murine models. Completion of these studies should identify the molecular mechanisms of AR- reduced LDAs in mediating carcinogenic signals, and lead to use of AR inhibitors as excellent chemopreventive drugs for CRC.HEALTH Relevance: colon cancer is the second leading cause of death among the cancer patients in US. Our project will determine the mechanisms of colon carcinogenesis, and ultimately lead to the development of new chemopreventive approaches to prevent death from colon cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA129383-03
Application #
7738905
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Perloff, Marjorie
Project Start
2007-12-01
Project End
2012-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
3
Fiscal Year
2010
Total Cost
$313,325
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Shukla, Kirtikar; Sonowal, Himangshu; Saxena, Ashish et al. (2017) Aldose reductase inhibitor, fidarestat regulates mitochondrial biogenesis via Nrf2/HO-1/AMPK pathway in colon cancer cells. Cancer Lett 411:57-63
Awasthi, Yogesh C; Ramana, Kota V; Chaudhary, Pankaj et al. (2017) Regulatory roles of glutathione-S-transferases and 4-hydroxynonenal in stress-mediated signaling and toxicity. Free Radic Biol Med 111:235-243
Sonowal, Himangshu; Pal, Pabitra B; Wen, Jian-Jun et al. (2017) Aldose reductase inhibitor increases doxorubicin-sensitivity of colon cancer cells and decreases cardiotoxicity. Sci Rep 7:3182
Saxena, Ashish; Tammali, Ravinder; Ramana, Kota V et al. (2017) Aldose reductase inhibitor, fidarestat prevents high-fat diet-induced intestinal polyps in ApcMin/+ mice. Curr Cancer Drug Targets :
Saxena, Ashish; Shoeb, Mohammad; Tammali, Ravinder et al. (2014) Aldose reductase inhibition suppresses azoxymethane-induced colonic premalignant lesions in C57BL/KsJ-db/db mice. Cancer Lett 355:141-7
Li, Yang; Zhao, Zhongxin; Xu, Chuanhui et al. (2014) HMGA2 induces transcription factor Slug expression to promote epithelial-to-mesenchymal transition and contributes to colon cancer progression. Cancer Lett 355:130-40
Shoeb, Mohammad; Ansari, Naseem H; Srivastava, Satish K et al. (2014) 4-Hydroxynonenal in the pathogenesis and progression of human diseases. Curr Med Chem 21:230-7
Shoeb, Mohammad; Ramana, Kota V; Srivastava, Satish K (2013) Aldose reductase inhibition enhances TRAIL-induced human colon cancer cell apoptosis through AKT/FOXO3a-dependent upregulation of death receptors. Free Radic Biol Med 63:280-90
Saxena, Ashish; Shoeb, Mohammad; Ramana, Kota V et al. (2013) Aldose reductase inhibition suppresses colon cancer cell viability by modulating microRNA-21 mediated programmed cell death 4 (PDCD4) expression. Eur J Cancer 49:3311-9
Saxena, Ashish; Tammali, Ravinder; Ramana, Kota V et al. (2013) Aldose Reductase Inhibition Prevents Colon Cancer Growth by Restoring Phosphatase and Tensin Homolog Through Modulation of miR-21 and FOXO3a. Antioxid Redox Signal 18:1249-62

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